GDF-15 Neutralization Alleviates Platinum-Based Chemotherapy-Induced Emesis, Anorexia, and Weight Loss in Mice and Nonhuman Primates
Danna M Breen, Hanna Kim, Donald Bennett, Roberto A Calle, Susie Collins, Ryan M Esquejo, Tao He, Stephanie Joaquim, Alison Joyce, Matthew Lambert, Laura Lin, Betty Pettersen, Shuxi Qiao, Michelle Rossulek, Gregory Weber, Zhidan Wu, Bei B Zhang, Morris J Birnbaum, Danna M Breen, Hanna Kim, Donald Bennett, Roberto A Calle, Susie Collins, Ryan M Esquejo, Tao He, Stephanie Joaquim, Alison Joyce, Matthew Lambert, Laura Lin, Betty Pettersen, Shuxi Qiao, Michelle Rossulek, Gregory Weber, Zhidan Wu, Bei B Zhang, Morris J Birnbaum
Abstract
Platinum-based cancer therapy is restricted by dose-limiting side effects and is associated with elevation of growth differentiation factor 15 (GDF-15). But whether this elevation contributes to such side effects has been unclear. Here, we explored the effects of GDF-15 blockade on platinum-based chemotherapy-induced emesis, anorexia, and weight loss in mice and/or nonhuman primate models. We found that circulating GDF-15 is higher in subjects with cancer receiving platinum-based chemotherapy and is positively associated with weight loss in colorectal cancer (NCT00609622). Further, chemotherapy agents associated with high clinical emetic score induce circulating GDF-15 and weight loss in mice. Platinum-based treatment-induced anorexia and weight loss are attenuated in GDF-15 knockout mice, while GDF-15 neutralization with the monoclonal antibody mAB1 improves survival. In nonhuman primates, mAB1 treatment attenuates anorexia and emesis. These results suggest that GDF-15 neutralization is a potential therapeutic approach to alleviate chemotherapy-induced side effects and improve the quality of life.
Keywords: chemotherapy; cisplatin; emesis; growth differentiation factor 15; survival; weight loss.
Conflict of interest statement
Declaration of Interests All authors are full-time employees of Pfizer Inc. D.B., M.J.B., R.A.C., B.P., and B.B.Z. are shareholders of Pfizer. M.R. has an immediate family member with management interests in Pfizer Inc. M.J.B. is a member of the Board of Directors of Cerevel. This manuscript relates to International Patent Application Publication No. WO2020/039321, which published February 27, 2020. Patent publication numbers US2020055930 and TW202021619 are both patent family members of the International Patent Application Publication No. WO2020/039321.
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Source: PubMed